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Idiopathic inflammatory myopathies (IIM) are a group of systemic autoimmune inflammatory disorders characterised by symmetrical skeletal muscle weakness and accelerated fatigue also in the early non-atrophic disease stage.1 Inflammatory cell infiltrates in the muscles are commonly present and important for diagnosing IIM. Yet, the degree of infiltrates does not correlate well with muscle weakness2 pointing to systemic factors as important mediators of muscle weakness in IIM.3 IgG autoantibodies are present in ~80% of patients with IIM and are important biomarkers used for subclassification and prognosis. It is debated if autoantibodies are mere biomarkers or play a causative role in disease development of IIM.4 Whether autoantibodies target the muscle (eg, circulating IgG targeting antigens within the muscle) thereby causing weakness in IIM is currently an open scientific question.
In this study, we investigated if sera or isolated IgG from patients with IIM may cause muscle weakness by directly impairing contractile function of muscle fibres.
To test our hypothesis that serum and autoantibodies could affect muscle force, we developed a humanised ex vivo experimental platform where muscles from healthy mice were exposed to sera from eight patients with IIM.5 Isolated flexor digitorum brevis (FDB) muscles were exposed to 10%–50% serum diluted in physiological solution from healthy controls or patients with IIM (n=8) (dermatomyositis, polymyositis and antisynthetase syndrome) (supplementary material, online supplemental table 1). In some experiments, muscles were exposed to isolated total IgG from autoantibody-positive patients (dermatomyositis and polymyositis). Measurements of force in whole muscles were performed before and 24 hours after incubation in serum or IgG. Muscle force and intracellular [Ca2+] …
Footnotes
Handling editor Josef S Smolen
Contributors CL, DCA and IEL contributed to the design of the study. All authors were involved in the acquisition of data. CL, DCA and IEL contributed to the analysis and interpretation of data. All authors contributed to drafting and/or revising the manuscript. DCA is the guarantor.
Funding DCA is supported by King Gustaf V 80-year foundation (FAI-2022-0935), Stiftelsen Promobilia (A23059), Stockholm County research grant (ALF; FoUI-1002205) and Swedish Heart-Lung Foundation (20230594). IEL was supported by Swedish Research Council (2020-01378), ALF (FoUI-955086), King Gustaf V 80-year foundation and Swedish Rheumatism Association. HA was supported by Swedish Research Council (2019-01111), ALF (20170271) and Swedish Rheumatism Association (858541, 931808).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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